Body temperature is highly regulated in mammals. However, thermal biology in smaller mammals (such as mice) is different from that in larger mammals (such as adult humans). For example, when mice are singly housed at room temperature, about half of caloric intake is burned to maintain body temperature (facultative thermogenesis), while humans require little facultative thermogenesis. Upon fasting, mice can reduce their body temperature by >10 C, while humans with extreme starvation lower body temperature by only 0.2 C. We are exploring the use of body temperature as an indicator of the perceived metabolic status of the mouse. For example, what is the effect on body temperature of a genetic manipulation or drug treatment? What genetic manipulations or drug treatments cause dissociation of body temperature from nutritional status? What are the neurotransmitters and neural mechanisms involved? Mice are also an ideal model system to study hypothermia, as the central regulatory mechanisms are likely conserved across mammals, but the mice show much greater changes than larger mammals. Thus, mice are a more sensitive species that can suggest studies that might be productively undertaken in larger individuals such as adult humans. We are interested in the neural control of body temperature and hypothermia, and in understanding pharmacologic inducers of hypothermia. Progress in FY2017 includes the following: We followed up on our prior studies showing that adenosine A3 receptor (A3AR) agonism causes hypothermia via peripheral mast cell activation, causing histamine release and activation of central histamine 1 receptors (1). We then showed that A1AR agonists acted centrally to cause hypothermia. In addition, we found that the commonly used A1AR agonist drugs were also agonizing A3AR and causing hypothermia via that mechanism, if given peripherally. The hypothermia causes by adenosine 5'-monophosphate (AMP) required neither A1AR nor A3AR. A1AR and A3AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A1AR nor A3AR was required for fasting-induced torpor. A1AR and A3AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms (2).